It is well established that glucose uptake and metabolism is greater in cancer cells than normal cells (Warburg (1956) Science 123:309-14). Furthermore, whereas normal cells use glucose for maximal ATP production in aerobic environments, malignant cells favor anaerobic metabolism, even in oxygen-rich environments; an observation made over 50 years ago and termed the “Warburg effect.” Malignant rapidly-growing cells typically have glycolytic rates many hundred times higher than cells of their normal tissues of origin. It is this distinguishing characteristic that has made it possible to identify malignant cells using 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) scanning (Gambhir (2002) Nat. Rev. Cancer 2:683-93). Since FDG is a hexokinase substrate, it is taken up in a higher concentration in some types of cancer cells compared to normal cells.
Similar to FDG, but without the radiotag, 2-deoxy-D-glucose (2DG) is a hexokinase substrate that competes with glucose for uptake via glucose transporters and is selectively taken up at higher concentrations in malignant cells (Simons, et al. (2009) J. Cancer Res. Ther. 5 Suppl 1:S2-6). 2DG, once phosphorylated, is incapable of further metabolism in the pentose cycle and blocks the cycle before the generation of pyruvate. It acts as a glycolysis inhibitor by both competitively and allosterically inhibiting hexokinase and competitively inhibiting phosphoisomerase (Crane & Sols (1954) J. Biol. Chem. 210:597-606; Liu, et al. (1999) J. Biol. Chem. 274:31155-9; Maher, et al. (2007) Mol. Cancer Ther. 6:732-41). This thereby inhibits glucose metabolism and creates a state of glucose deprivation within the cell.
Cancer therapeutics predominantly act by inducing apoptosis via the intrinsic or extrinsic pathway. The intrinsic apoptotic pathway capitalizes on cytotoxic stress to form the apoptosome complex and is enhanced by radiation and certain chemotherapies (Adrain & Martin (2001) Trends Biochem. Sci. 26:390-7; Cain, et al. (2002) Biochimie 84:203-14). The extrinsic pathway is initiated by extracellular binding of tumor necrosis factor (TNF) members, including TNF-related apoptosis inducing ligand (TRAIL) to transmembrane death receptors (Wallach, et al. (1999) Annu. Rev. Immunol. 17:331-67). 2DG has been shown to increase sensitivity to TRAIL-induced apoptosis, even in TRAIL-resistant cancer cell lines (Liu, et al. (2009) Mol. Cancer 8:122; Qin, et al. (2010) Biochem. Biophys. Res. Commun. 401:293-9; MacFarlane, et al. (2012) Cell Cycle 11:3919-25).
Colon cancer is known to be a PET-avid malignancy, and the use of FDG-PET scanning has become critical in management of these patients, especially in identifying colorectal liver metastases (Wiering, et al. (2005) Cancer 104:2658-70). The current model of treating metastatic colorectal cancer involves a combination of surgery and chemotherapy. Surgery can only be performed on a minority of patients and the majority of these patients will experience tumor recurrence and die of disease (Tomlinson, et al. (2007) J. Clin. Oncol. 25:4575-80). Chemotherapy has inherent morbidity that prohibits use in patients with significant co-morbidities, and the best current regimens provides on average less than two-years of survival for patients with colorectal liver metastases. Therefore, new therapeutic approaches are needed.